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2.  DNA Copy Number Variants of Known Glaucoma Genes in Relation to Primary Open-Angle Glaucoma 
Purpose.
We examined the role of DNA copy number variants (CNVs) of known glaucoma genes in relation to primary open angle glaucoma (POAG).
Methods.
Our study included DNA samples from two studies (NEIGHBOR and GLAUGEN). All the samples were genotyped with the Illumina Human660W_Quad_v1 BeadChip. After removing non–blood-derived and amplified DNA samples, we applied quality control steps based on the mean Log R Ratio and the mean B allele frequency. Subsequently, data from 3057 DNA samples (1599 cases and 1458 controls) were analyzed with PennCNV software. We defined CNVs as those ≥5 kilobases (kb) in size and interrogated by ≥5 consecutive probes. We further limited our investigation to CNVs in known POAG-related genes, including CDKN2B-AS1, TMCO1, SIX1/SIX6, CAV1/CAV2, the LRP12-ZFPM2 region, GAS7, ATOH7, FNDC3B, CYP1B1, MYOC, OPTN, WDR36, SRBD1, TBK1, and GALC.
Results.
Genomic duplications of CDKN2B-AS1 and TMCO1 were each found in a single case. Two cases carried duplications in the GAS7 region. Genomic deletions of SIX6 and ATOH7 were each identified in one case. One case carried a TBK1 deletion and another case carried a TBK1 duplication. No controls had duplications or deletions in these six genes. A single control had a duplication in the MYOC region. Deletions of GALC were observed in five cases and two controls.
Conclusions.
The CNV analysis of a large set of cases and controls revealed the presence of rare CNVs in known POAG susceptibility genes. Our data suggest that these rare CNVs may contribute to POAG pathogenesis and merit functional evaluation.
Our study examined DNA copy number variants of known glaucoma genes in two large cohorts - NEIGHBOR and GLAUGEN. We identified rare deletions and/or duplications in a few glaucoma genes only in POAG cases. Our data suggest potential role of these rare CNVs in POAG pathogenesis.
doi:10.1167/iovs.14-15712
PMCID: PMC4271633  PMID: 25414181
DNA copy number variants; POAG; genetics; SIX6; GAS7
3.  Handheld Optical Coherence Tomography During Sedation in Young Children With Optic Pathway Gliomas 
JAMA ophthalmology  2014;132(3):265-271.
IMPORTANCE
Monitoring young children with optic pathway gliomas (OPGs) for visual deterioration can be difficult owing to age-related noncompliance. Optical coherence tomography (OCT) measures of retinal nerve fiber layer (RNFL) thickness have been proposed as a surrogate marker of vision but this technique is also limited by patient cooperation.
OBJECTIVE
To determine whether measures of circumpapillary RNFL thickness, acquired with handheld OCT (HH-OCT) during sedation, can differentiate between young children with and without vision loss from OPGs.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional analysis of a prospective observational study was conducted at a tertiary-care children’s hospital. Children with an OPG (sporadic or secondary to neurofibromatosis type 1) who were cooperative for visual acuity testing, but required sedation to complete magnetic resonance imaging, underwent HH-OCT imaging of the circumpapillary RNFL while sedated.
MAIN OUTCOMES AND MEASURES
Area under the curve of the receiver operating characteristic, sensitivity, specificity, positive predictive value, and negative predictive value of the average and quadrant-specific RNFL thicknesses.
RESULTS
Thirty-three children (64 eyes) met inclusion criteria (median age, 4.8 years; range, 1.8–12.6 years). In children with vision loss (abnormal visual acuity and/or visual field), RNFL thickness was decreased in all quadrants compared with the normal-vision group (P < .001 for all comparisons). Using abnormal criteria of less than 5% and less than 1%, the area under the curve was highest for the average RNFL thickness (0.96 and 0.97, respectively) compared with specific anatomic quadrants. The highest discrimination and predictive values were demonstrated for participants with 2 or more quadrants meeting less than 5% (sensitivity = 93.3; specificity = 97.9; positive predictive value = 93.3; and negative predictive value = 97.9) and less than 1% (sensitivity = 93.3; specificity = 100; positive predictive value = 100; and negative predictive value = 98.0) criteria.
CONCLUSIONS AND RELEVANCE
Measures of RNFL thickness acquired with HH-OCT during sedation can differentiate between young children with and without vision loss from OPGs. For young children who do not cooperate with vision testing, HH-OCT measures may be a surrogate marker of vision. Longitudinal studies are needed to delineate the temporal relationship between RNFL decline and vision loss.
doi:10.1001/jamaophthalmol.2013.7649
PMCID: PMC4445404  PMID: 24435762
4.  Lymphoma of the orbit masquerading as Tolosa-Hunt syndrome 
BMC Ophthalmology  2015;15:51.
Background
Tolosa-Hunt syndrome is a rare clinical syndrome characterized by painful ophthalmoplegia and ipsilateral cranial neuropathies. It is caused by an inflammatory process of unknown etiology.
Case presentation
We present a case of a 77-year-old white man with history of Waldenstrom’s macroglobulinemia transforming to large B-cell lymphoma who presented to a community physician complaining of 4 months of isolated right retro-orbital pain and later with diplopia, ptosis, 6th nerve and pupil-sparing partial 3rd nerve palsies as well as progressive neurological findings. His clinical course was complicated by debilitating neurological symptoms and multiple hospitalizations leading to a delay in diagnosis caused by incomplete initial workup.
Conclusion
This case is a reminder that lymphoproliferative disorders often mimic other neurologic disorders and that Tolosa-Hunt is a rare diagnosis that must be considered a diagnosis of exclusion.
doi:10.1186/s12886-015-0037-8
PMCID: PMC4450859  PMID: 25971316
Lymphoma; Tolosa-Hunt; Neuro-imaging; Cavernous sinus; MRI
5.  In Vivo Three-Dimensional Characterization of the Healthy Human Lamina Cribrosa With Adaptive Optics Spectral-Domain Optical Coherence Tomography 
Purpose.
To characterize the in vivo three-dimensional (3D) lamina cribrosa (LC) microarchitecture of healthy eyes using adaptive optics spectral-domain optical coherence tomography (AO-SDOCT).
Methods.
A multimodal retinal imaging system with a light source centered at 1050 nm and AO confocal scanning laser ophthalmoscopy was used in this study. One randomly selected eye from 18 healthy subjects was scanned in a 6° × 6° window centered on the LC. Subjects also underwent scanning with Cirrus HD-OCT. Lamina cribrosa microarchitecture was semiautomatically segmented and quantified for connective tissue volume fraction (CTVF), beam thickness, pore diameter, pore area, and pore aspect ratio. The LC was assessed in central and peripheral regions of equal areas and quadrants and with depth. A linear mixed effects model weighted by the fraction of visible LC was used to compare LC structure between regions.
Results.
The nasal quadrant was excluded due to poor visualization. The central sector showed greater CTVF and thicker beams as compared to the periphery (P < 0.01). Both superior and inferior quadrants showed greater CTVF, pore diameter, and pore mean area than the temporal quadrant (P < 0.05). Depth analysis showed that the anterior and posterior aspects of the LC contained smaller pores with greater density and thinner beams as compared to the middle third (P < 0.05). The anterior third also showed a greater CTVF than the middle third (P < 0.05).
Conclusions.
In vivo analysis of healthy eyes using AO-SDOCT showed significant, albeit small, regional variation in LC microarchitecture by quadrant, radially, and with depth, which should be considered in further studies of the LC.
This paper describes the three-dimensional microarchitecture of the healthy lamina cribrosa scanned in vivo using adaptive optics spectral-domain optical coherence tomography.
doi:10.1167/iovs.14-15177
PMCID: PMC4197769  PMID: 25228539
in vivo; OCT; structure
6.  Magic Angle–Enhanced MRI of Fibrous Microstructures in Sclera and Cornea With and Without Intraocular Pressure Loading 
Purpose.
The structure and biomechanics of the sclera and cornea are central to several eye diseases such as glaucoma and myopia. However, their roles remain unclear, partly because of limited noninvasive techniques to assess their fibrous microstructures globally, longitudinally, and quantitatively. We hypothesized that magic angle–enhanced magnetic resonance imaging (MRI) can reveal the structural details of the corneoscleral shell and their changes upon intraocular pressure (IOP) elevation.
Methods.
Seven ovine eyes were extracted and fixed at IOP = 50 mm Hg to mimic ocular hypertension, and another 11 eyes were unpressurized. The sclera and cornea were scanned at different angular orientations relative to the main magnetic field inside a 9.4-Tesla MRI scanner. Relative MRI signal intensities and intrinsic transverse relaxation times (T2 and T2*) were determined to quantify the magic angle effect on the corneoscleral shells. Three loaded and eight unloaded tendon samples were scanned as controls.
Results.
At magic angle, high-resolution MRI revealed distinct scleral and corneal lamellar fibers, and light/dark bands indicative of collagen fiber crimps in the sclera and tendon. Magic angle enhancement effect was the strongest in tendon and the least strong in cornea. Loaded sclera, cornea, and tendon possessed significantly higher T2 and T2* than unloaded tissues at magic angle.
Conclusions.
Magic angle–enhanced MRI can detect ocular fibrous microstructures without contrast agents or coatings and can reveal their MR tissue property changes with IOP loading. This technique may open up new avenues for assessment of the biomechanical and biochemical properties of ocular tissues in aging and in diseases involving the corneoscleral shell.
Magic angle–enhanced MRI can detect fibrous microstructures such as lamellar fibers and collagen fiber crimps in the sclera and cornea without contrast agents or coatings. The magic angle effect improves MRI sensitivity for quantifying differences between normal and IOP-loaded ocular tissues.
doi:10.1167/iovs.14-14561
PMCID: PMC4160095  PMID: 25103267
magic angle effect; magnetic resonance imaging; sclera; cornea; ocular hypertension
7.  Combining Information from Three Anatomic Regions in the Diagnosis of Glaucoma with Time-Domain Optical Coherence Tomography 
Journal of glaucoma  2014;23(3):129-135.
Purpose
To improve the diagnosis of glaucoma by combining time-domain optical coherence tomography (TD-OCT) measurements of the optic disc, circumpapillary retinal nerve fiber layer (RNFL), and macular retinal thickness.
Patients and Methods
Ninety-six age-matched normal and 96 perimetric glaucoma participants were included in this observational, cross-sectional study. Or-logic, support vector machine (SVM), relevance vector machine (RVM), and linear discrimination function (LDF) were used to analyze the performances of combined TD-OCT diagnostic variables.
Results
The area under the receiver operating curve (AROC) was used to evaluate the diagnostic accuracy and to compare the diagnostic performance of single and combined anatomic variables. The best RNFL thickness variables were the inferior (AROC=0.900), overall (AROC=0.892), and superior quadrants (AROC=0.850). The best optic disc variables were horizontal integrated rim width (AROC=0.909), vertical integrated rim area (AROC=0.908), and cup/disc vertical ratio (AROC=0.890). All macular retinal thickness variables had AROCs of 0.829 or less. Combining the top 3 RNFL and optic disc variables in optimizing glaucoma diagnosis, SVM had the highest AROC, 0.954, followed by or-logic (AROC=0.946), LDF (AROC=0.946), and RVM (AROC=0.943). All combination diagnostic variables had significantly larger AROCs than any single diagnostic variable. There are no significant differences among the combination diagnostic indices.
Conclusions
With TD-OCT, RNFL and optic disc variables had better diagnostic accuracy than macular retinal variables. Combining top RNFL and optic disc variables significantly improved diagnostic performance. Clinically, or-logic classification was the most practical analytical tool with sufficient accuracy to diagnose early glaucoma.
doi:10.1097/IJG.0b013e318264b941
PMCID: PMC3535579  PMID: 22828002
optical coherence tomography; glaucoma; imaging; image processing
8.  In Vivo Assessment of Aqueous Humor Dynamics Upon Chronic Ocular Hypertension and Hypotensive Drug Treatment Using Gadolinium-Enhanced MRI 
Purpose.
Although glaucoma treatments alter aqueous humor (AH) dynamics to lower intraocular pressure, the regulatory mechanisms of AH circulation and their contributions to the pathogenesis of ocular hypertension and glaucoma remain unclear. We hypothesized that gadolinium-enhanced magnetic resonance imaging (Gd-MRI) can visualize and assess AH dynamics upon sustained intraocular pressure elevation and pharmacologic interventions.
Methods.
Gadolinium contrast agent was systemically administered to adult rats to mimic soluble AH components entering the anterior chamber (AC) via blood–aqueous barrier. Dynamic Gd-MRI was applied to examine the signal enhancement in AC and vitreous body upon microbead-induced ocular hypertension and unilateral topical applications of latanoprost, timolol maleate, and brimonidine tartrate to healthy eyes.
Results.
Gadolinium signal time courses in microbead-induced hypertensive eyes possessed faster initial gadolinium uptake and higher peak signals in AC than control eyes, reflective of reduced gadolinium clearance upon microbead occlusion. Opposite trends were observed in latanoprost- and timolol-treated eyes, indicative of their respective drug actions on increased uveoscleral outflow and reduced AH production. The slowest initial gadolinium uptake but strongest peak signals were found in AC of both brimonidine-treated and untreated fellow eyes. These findings drew attention to the systemic effects of topical hypotensive drug treatment. Gadolinium leaked into the vitreous of microbead-induced hypertensive eyes and brimonidine-treated and untreated fellow eyes, suggestive of a compromise of aqueous–vitreous or blood–ocular barrier integrity.
Conclusions.
Gadolinium-enhanced MRI allows spatiotemporal and quantitative evaluation of altered AH dynamics and ocular tissue permeability for better understanding the physiological mechanisms of ocular hypertension and the efficacy of antiglaucoma drug treatments.
Gadolinium-enhanced MRI allows spatiotemporal and quantitative evaluation of altered aqueous humor dynamics and ocular tissue permeability upon chronic ocular hypertension and pharmacologic interventions. It also reveals the systemic effects of topical hypotensive drugs during glaucoma treatment.
doi:10.1167/iovs.14-14263
PMCID: PMC4062398  PMID: 24764067
gadolinium; magnetic resonance imaging; aqueous humor dynamics; ocular tissue permeability; intraocular pressure
9.  OCT for glaucoma diagnosis, screening and detection of glaucoma progression 
The British Journal of Ophthalmology  2013;98(Suppl 2):ii15-ii19.
Optical coherence tomography (OCT) is a commonly used imaging modality in the evaluation of glaucomatous damage. The commercially available spectral domain (SD)-OCT offers benefits in glaucoma assessment over the earlier generation of time domain-OCT due to increased axial resolution, faster scanning speeds and has been reported to have improved reproducibility but similar diagnostic accuracy. The capabilities of SD-OCT are rapidly advancing with 3D imaging, reproducible registration, and advanced segmentation algorithms of macular and optic nerve head regions. A review of the evidence to date suggests that retinal nerve fibre layer remains the dominant parameter for glaucoma diagnosis and detection of progression while initial studies of macular and optic nerve head parameters have shown promising results. SD-OCT still currently lacks the diagnostic performance for glaucoma screening.
doi:10.1136/bjophthalmol-2013-304326
PMCID: PMC4208340  PMID: 24357497
Glaucoma
10.  Characterisation of Schlemm's canal cross-sectional area 
The British Journal of Ophthalmology  2014;98(Suppl 2):ii10-ii14.
Purpose
To compare three methods of Schlemm's canal (SC) cross-sectional area (CSA) measurement.
Methods
Ten eyes (10 healthy volunteers) were imaged three times using spectral-domain optical coherence tomography (Cirrus HD-OCT, Zeiss, Dublin, California, USA). Aqueous outflow vascular structures and SC collector channel ostia were used as landmarks to identify a reference location within the limbus. SC CSA was assessed within a 1 mm segment (±15 frames of the reference, 31 frames in all) by three techniques. (1) Using a random number table, SC CSA in five random frames from the set of 31 surrounding the reference were measured and averaged. (2) The most easily visualised SC location (subjective) was measured, and (3) SC CSA was measured in all 31 consecutive B-scans, and averaged. (comprehensive average, gold standard). Subjective and random CSAs were compared with the comprehensive by general estimating equation modelling, and structural equation modelling quantified agreement.
Results
The average from five random locations (4175±1045 µm2) was not significantly different than that obtained from the gold standard comprehensive assessment (4064±1308 µm2, p=0.6537). Subjectively located SC CSA (7614±2162 µm2) was significantly larger than the comprehensive gold standard SC CSA (p<0.0001). The average of five random frames produced significantly less bias than did subjective location, yielding a calibration line crossing the ‘no-bias’ line.
Discussion
Subjectively located SC CSA measurements produce high estimates of SC CSA. SC assessed by measuring five random locations estimate CSA was similar to the gold standard estimate.
doi:10.1136/bjophthalmol-2013-304629
PMCID: PMC4208345  PMID: 24590558
Aqueous humour; Imaging
11.  A Laser-Induced Mouse Model with Long-Term Intraocular Pressure Elevation 
PLoS ONE  2014;9(9):e107446.
Purpose
To develop and characterize a mouse model with intraocular pressure (IOP) elevation after laser photocoagulation on the trabecular meshwork (TM), which may serve as a model to investigate the potential of stem cell-based therapies for glaucoma.
Methods
IOP was measured in 281 adult C57BL/6 mice to determine normal IOP range. IOP elevation was induced unilaterally in 50 adult mice, by targeting the TM through the limbus with a 532-nm diode laser. IOP was measured up to 24 weeks post-treatment. The optic nerve damage was detected by electroretinography and assessed by semiautomatic counting of optic nerve axons. Effects of laser treatment on the TM were evaluated by histology, immunofluorescence staining, optical coherence tomography (OCT) and transmission electron microscopy (TEM).
Results
The average IOP of C57BL/6 mice was 14.5±2.6 mmHg (Mean ±SD). After laser treatment, IOP averaged above 20 mmHg throughout the follow-up period of 24 weeks. At 24 weeks, 57% of treated eyes had elevated IOP with the mean IOP of 22.5±2.5 mmHg (Mean ±SED). The difference of average axon count (59.0%) between laser treated and untreated eyes was statistically significant. Photopic negative response (PhNR) by electroretinography was significantly decreased. CD45+ inflammatory cells invaded the TM within 1 week. The expression of SPARC was increased in the TM from 1 to 12 weeks. Histology showed the anterior chamber angle open after laser treatment. OCT indicated that most of the eyes with laser treatment had no synechia in the anterior chamber angles. TEM demonstrated disorganized and compacted extracellular matrix in the TM.
Conclusions
An experimental murine ocular hypertension model with an open angle and optic nerve axon loss was produced with laser photocoagulation, which could be used to investigate stem cell-based therapies for restoration of the outflow pathway integrity for ocular hypertension or glaucoma.
doi:10.1371/journal.pone.0107446
PMCID: PMC4162591  PMID: 25216052
12.  The NEIGHBOR Consortium Primary Open Angle Glaucoma Genome-wide Association Study: Rationale, Study design and Clinical variables 
Journal of glaucoma  2013;22(7):517-525.
Primary open-angle glaucoma (POAG) is a common disease with complex inheritance. The identification of genes predisposing to POAG is an important step toward the development of novel gene-based methods of diagnosis and treatment. Genome-wide association studies (GWAS) have successfully identified genes contributing to complex traits such as POAG however, such studies frequently require very large sample sizes, and thus, collaborations and consortia have been of critical importance for the GWAS approach. In this report we describe the formation of the NEIGHBOR consortium, the harmonized case control definitions used for a POAG GWAS, the clinical features of the cases and controls and the rationale for the GWAS study design.
doi:10.1097/IJG.0b013e31824d4fd8
PMCID: PMC3485429  PMID: 22828004
13.  IOP Elevation Reduces Schlemm's Canal Cross-Sectional Area 
Purpose.
Previously, we demonstrated reduced Schlemm's canal cross-sectional area (SC-CSA) with increased perfusion pressure in a cadaveric flow model. The purpose of the present study was to determine the effect of acute IOP elevation on SC-CSA in living human eyes.
Methods.
The temporal limbus of 27 eyes of 14 healthy subjects (10 male, 4 female, age 36 ± 13 years) was imaged by spectral-domain optical coherence tomography at baseline and with IOP elevation (ophthalmodynamometer set at 30-g force). Intraocular pressure was measured at baseline and with IOP elevation by Goldmann applanation tonometry. Vascular landmarks were used to identify corresponding locations in baseline and IOP elevation scan volumes. Schlemm's canal CSA at five locations within a 1-mm length of SC was measured in ImageJ as described previously. A linear mixed-effects model quantified the effect of IOP elevation on SC-CSA.
Results.
The mean IOP increase was 189%, and the mean SC-CSA decrease was 32% (P < 0.001). The estimate (95% confidence interval) for SC-CSA response to IOP change was −66.6 (−80.6 to −52.7) μm2/mm Hg.
Conclusions.
Acute IOP elevation significantly reduces SC-CSA in healthy eyes. Acute dynamic response to IOP elevation may be a useful future characterization of ocular health in the management of glaucoma.
Visualization of a stress strain response in the aqueous humor outflow tract is presented. Using an ophthalmodynamometer to create an acute IOP increase in normal healthy eyes, morphometric changes in Schlemm's canal can be observed and quantified in OCT imagery.
doi:10.1167/iovs.13-13264
PMCID: PMC3968930  PMID: 24526436
ophthalmodynamometer; optical coherence tomography; outflow tract imaging
14.  There has to be a better way evolution of internal filtration glaucoma surgeries 
The British journal of ophthalmology  2013;97(10):1228-1229.
doi:10.1136/bjophthalmol-2013-303237
PMCID: PMC4122115  PMID: 24049122
15.  Outflow Tract Ablation Using a Conditionally Cytotoxic Feline Immunodeficiency Viral Vector 
Purpose.
To create an in vivo model of vector-mediated trabecular meshwork (TM) ablation and replacement.
Methods.
We generated a conditionally cytotoxic, trackable vector, HSVtkiG, that expressed herpes simplex virus 1 thymidine kinase (HSVtk) and enhanced green fluorescent protein (eGFP). We optimized HSVtkiG ablation in vitro with ganciclovir (GCV) in comparison to eGFP control vector GINSIN and investigated the mechanism. Right eyes of 24 rats were then injected intracamerally with either HSVtkiG or GINSIN, before intraperitoneal GCV was administered 1 week later. Intraocular pressure, central corneal thickness (CCT), and slit-lamp exams were assessed for 8 weeks. Transduction and ablation were followed by gonioscopic visualization of eGFP. Histology was obtained with TM cell counts and immunohistochemistry markers of inflammation.
Results.
Transduction and ablation parameters were established in vitro. Apoptosis was the cause of cell death. In vivo, transduction was seen gonioscopically to be targeted to the TM, followed by disappearance of eGFP marker fluorescence in HSVtkiG-transduced cells after injection of GCV. Ablation resulted in an IOP decrease of 25% in HSVtkiG-injected eyes 2 days after GCV but not in GINSIN or noninjected control eyes (P < 0.05). Trabecular meshwork cellularity was decreased at the time of lowest IOP and recovered thereafter, while CCT remained unchanged. Inflammation was absent.
Conclusions.
A vector-based system for inducible ablation of cells of the outflow tract was developed. Trabecular meshwork ablation lowered IOP, and recovery of cellularity and IOP followed. This model may be useful to study pressure regulation by the TM, its stem cells, and migration patterns.
We used an in vivo trackable, conditionally cytotoxic feline immunodeficiency viral (FIV) vector with an HSVtk cassette to ablate the trabecular meshwork in the rat. Ablation lowered IOP, and recovery of cellularity followed. This model may be useful to study pressure regulation by the TM, its stem cells, and migration patterns.
doi:10.1167/iovs.13-12890
PMCID: PMC3929079  PMID: 24448264
glaucoma; trabecular meshwork; gene therapy; ablation
16.  Quantitative 3D-OCT motion correction with tilt and illumination correction, robust similarity measure and regularization 
Biomedical Optics Express  2014;5(8):2591-2613.
Variability in illumination, signal quality, tilt and the amount of motion pose challenges for post-processing based 3D-OCT motion correction algorithms. We present an advanced 3D-OCT motion correction algorithm using image registration and orthogonal raster scan patterns aimed at addressing these challenges. An intensity similarity measure using the pseudo Huber norm and a regularization scheme based on a pseudo L0.5 norm are introduced. A two-stage registration approach was developed. In the first stage, only axial motion and axial tilt are coarsely corrected. This result is then used as the starting point for a second stage full optimization. In preprocessing, a bias field estimation based approach to correct illumination differences in the input volumes is employed. Quantitative evaluation was performed using a large set of data acquired from 73 healthy and glaucomatous eyes using SD-OCT systems. OCT volumes of both the optic nerve head and the macula region acquired with three independent orthogonal volume pairs for each location were used to assess reproducibility. The advanced motion correction algorithm using the techniques presented in this paper was compared to a basic algorithm corresponding to an earlier version and to performing no motion correction. Errors in segmentation-based measures such as layer positions, retinal and nerve fiber thickness, as well as the blood vessel pattern were evaluated. The quantitative results consistently show that reproducibility is improved considerably by using the advanced algorithm, which also significantly outperforms the basic algorithm. The mean of the mean absolute retinal thickness difference over all data was 9.9 um without motion correction, 7.1 um using the basic algorithm and 5.0 um using the advanced algorithm. Similarly, the blood vessel likelihood map error is reduced to 69% of the uncorrected error for the basic and to 47% of the uncorrected error for the advanced algorithm. These results demonstrate that our advanced motion correction algorithm has the potential to improve the reliability of quantitative measurements derived from 3D-OCT data substantially.
doi:10.1364/BOE.5.002591
PMCID: PMC4132991  PMID: 25136488
(170.4500) Optical coherence tomography; (170.4470) Ophthalmology; (100.2980) Image enhancement; (100.5010) Pattern recognition
17.  In Vivo Lamina Cribrosa Micro-Architecture in Healthy and Glaucomatous Eyes as Assessed by Optical Coherence Tomography 
Purpose.
The lamina cribrosa (LC) is a prime location of glaucomatous damage. The purpose of this study was to compare LC 3-dimensional micro-architecture between healthy and glaucomatous eyes in vivo by using optical coherence tomography (OCT).
Methods.
Sixty-eight eyes (19 healthy and 49 glaucomatous) from 47 subjects were scanned in a 3.5 × 3.5 × 3.64-mm volume (400 × 400 × 896 pixels) at the optic nerve head by using swept-source OCT. The LC micro-architecture parameters were measured on the visible LC by an automated segmentation algorithm. The LC parameters were compared to diagnosis and visual field mean deviation (VF MD) by using a linear mixed effects model accounting for age.
Results.
The average VF MD for the healthy and glaucomatous eyes was −0.50 ± 0.80 dB and −7.84 ± 8.75 dB, respectively. Beam thickness to pore diameter ratio (P = 0.04) and pore diameter standard deviation (P < 0.01) were increased in glaucomatous eyes. With worse MD, beam thickness to pore diameter ratio (P < 0.01), pore diameter standard deviation (P = 0.05), and beam thickness (P < 0.01) showed a statistically significant increase while pore diameter (P = 0.02) showed a significant decrease. There were no significant interactions between any of the parameters and age (all P > 0.05).
Conclusions.
Glaucomatous micro-architecture changes in the LC, detected by OCT analysis, reflect beams remodeling and axonal loss leading to reduction in pore size and increased pore size variability.
Using swept-source OCT we demonstrated in vivo significant differences in the lamina cribrosa micro-architecture between healthy and glaucomatous eyes. These changes reflect beams remodeling and axonal loss leading to reduction in pore size and increased pore size variability.
doi:10.1167/iovs.13-13109
PMCID: PMC3869422  PMID: 24302585
lamina cribrosa; optical coherence tomography; glaucoma
18.  Reproducibility of In-Vivo OCT Measured Three-Dimensional Human Lamina Cribrosa Microarchitecture 
PLoS ONE  2014;9(4):e95526.
Purpose
To determine the reproducibility of automated segmentation of the three-dimensional (3D) lamina cribrosa (LC) microarchitecture scanned in-vivo using optical coherence tomography (OCT).
Methods
Thirty-nine eyes (8 healthy, 19 glaucoma suspects and 12 glaucoma) from 49 subjects were scanned twice using swept-source (SS−) OCT in a 3.5×3.5×3.64 mm (400×400×896 pixels) volume centered on the optic nerve head, with the focus readjusted after each scan. The LC was automatically segmented and analyzed for microarchitectural parameters, including pore diameter, pore diameter standard deviation (SD), pore aspect ratio, pore area, beam thickness, beam thickness SD, and beam thickness to pore diameter ratio. Reproducibility of the parameters was assessed by computing the imprecision of the parameters between the scans.
Results
The automated segmentation demonstrated excellent reproducibility. All LC microarchitecture parameters had an imprecision of less or equal to 4.2%. There was little variability in imprecision with respect to diagnostic category, although the method tends to show higher imprecision amongst healthy subjects.
Conclusion
The proposed automated segmentation of the LC demonstrated high reproducibility for 3D LC parameters. This segmentation analysis tool will be useful for in-vivo studies of the LC.
doi:10.1371/journal.pone.0095526
PMCID: PMC3991692  PMID: 24747957
19.  Repeatability of in vivo 3D lamina cribrosa microarchitecture using adaptive optics spectral domain optical coherence tomography 
Biomedical Optics Express  2014;5(4):1114-1123.
We demonstrate the repeatability of lamina cribrosa (LC) microarchitecture for in vivo 3D optical coherence tomography (OCT) scans of healthy, glaucoma suspects, and glaucomatous eyes. Eyes underwent two scans using a prototype adaptive optics spectral domain OCT (AO-SDOCT) device from which LC microarchitecture was semi-automatically segmented. LC segmentations were used to quantify pore and beam structure through several global microarchitecture parameters. Repeatability of LC microarchitecture was assessed qualitatively and quantitatively by calculating parameter imprecision. For all but one parameters (pore volume) measurement imprecision was <4.7% of the mean value, indicating good measurement reproducibility. Imprecision ranged between 27.3% and 54.5% of the population standard deviation for each parameter, while there was not a significant effect on imprecision due to disease status, indicating utility in testing for LC structural trends.
doi:10.1364/BOE.5.001114
PMCID: PMC3986004  PMID: 24761293
(100.2000) Digital image processing; (170.4470) Ophthalmology; (110.4500) Optical coherence tomography; (170.1610) Clinical applications; (330.4460) Ophthalmic optics and devices
20.  Gold Nanorods as a Contrast Agent for Doppler Optical Coherence Tomography 
PLoS ONE  2014;9(3):e90690.
Purpose
To investigate gold nanorods (GNRs) as a contrast agent to enhance Doppler optical coherence tomography (OCT) imaging of the intrascleral aqueous humor outflow.
Methods
A serial dilution of GNRs was scanned with a spectral-domain OCT device (Bioptigen, Durham, NC) to visualize Doppler signal. Doppler measurements using GNRs were validated using a controlled flow system. To demonstrate an application of GNR enhanced Doppler, porcine eyes were perfused at constant pressure with mock aqueous alone or 1.0×1012 GNR/mL mixed with mock aqueous. Twelve Doppler and volumetric SD-OCT scans were obtained from the limbus in a radial fashion incremented by 30°, forming a circular scan pattern. Volumetric flow was computed by integrating flow inside non-connected vessels throughout all 12 scans around the limbus.
Results
At the GNR concentration of 0.7×1012 GNRs/mL, Doppler signal was present through the entire depth of the testing tube without substantial attenuation. A well-defined laminar flow profile was observed for Doppler images of GNRs flowing through the glass capillary tube. The Doppler OCT measured flow profile was not statistically different from the expected flow profile based upon an autoregressive moving average model, with an error of −0.025 to 0.037 mm/s (p = 0.6435). Cross-sectional slices demonstrated the ability to view anterior chamber outflow ex-vivo using GNR-enhanced Doppler OCT. Doppler volumetric flow measurements were comparable to flow recorded by the perfusion system.
Conclusions
GNRs created a measureable Doppler signal within otherwise silent flow fields in OCT Doppler scans. Practical application of this technique was confirmed in a constant pressure ex-vivo aqueous humor outflow model in porcine eyes.
doi:10.1371/journal.pone.0090690
PMCID: PMC3940929  PMID: 24595044
21.  CDKN2B-AS1 Genotype – Glaucoma Feature Correlations in Primary Open-Angle Glaucoma Patients from the United States 
American journal of ophthalmology  2012;155(2):342-353.e5.
PURPOSE
To assess the association between single nucleotide polymorphisms (SNPs) of the gene region containing cyclin dependent kinase inhibitor 2B antisense noncoding RNA (CDKN2B-AS1) and glaucoma features among primary open-angle glaucoma (POAG) patients.
DESIGN
Retrospective observational case series.
METHODS
We studied associations between ten CDKN2B-AS1 SNPs and glaucoma features among 976 POAG cases from the Glaucoma Genes and Environment (GLAUGEN) study and 1971 cases from the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium. For each patient, we chose the feature from the eye with the higher value. We created cohort-specific multivariable models for glaucoma features and then meta-analyzed the results.
RESULTS
For nine of the ten protective CDKN2B-AS1 SNPs with minor alleles associated with reduced disease risk (e.g., the G allele at rs2157719), POAG patients carrying these minor alleles had smaller cup-disc ratio (0.05 units smaller per G allele at diagnosis; 95% CI: −0.08, −0.03; p=6.23E-05) despite having higher intraocular pressure (IOP) (0.70 mm Hg higher per G allele at DNA collection; 95% CI: 0.40, 1.00; P=5.45E-06). For the one adverse rs3217992 SNP with minor allele A associated with increased disease risk, POAG patients with A alleles had larger cup-disc ratio (0.05 units larger per A allele at diagnosis; 95% CI: 0.02, 0.07; P=4.74E-04) despite having lower IOP (−0.57 mm Hg per A allele at DNA collection; 95% CI: −0.84, −0.29; P=6.55E-05).
CONCLUSION
Alleles of CDKN2B-AS1 SNPs, which influence risk of developing POAG, also modulate optic nerve degeneration among POAG patients, underscoring the role of CDKN2B-AS1 in POAG.
doi:10.1016/j.ajo.2012.07.023
PMCID: PMC3544983  PMID: 23111177
22.  Retinal Nerve Fiber Layer Atrophy Is Associated with Visual Field Loss over Time in Glaucoma Suspect and Glaucomatous Eyes 
American journal of ophthalmology  2012;155(1):73-82.e1.
Purpose
To prospectively compare detection of progressive retinal nerve fiber layer thickness (RNFL) atrophy identified using time-domain optical coherence tomography (OCT) with visual field progression using standard automated perimetry (SAP) in glaucoma suspect and preperimetric glaucoma and perimetric glaucoma patients.
Design
Prospective longitudinal clinical trial
Methods
Eligible eyes with ≥2 years of follow-up underwent time-domain OCT and SAP every 6 months. The occurrence of visual field progression was defined as the first follow-up visit reaching a significant (p<0.05) negative visual field index (VFI) slope over time. RNFL progression/improvement was defined as a significant negative/positive slope over time. Specificity was defined as the number of eyes with neither progression nor improvement, divided by the number of eyes without progression. Cox proportional hazard ratios (HR) were calculated using univariate and multivariate models with RNFL loss as a time-dependent covariate.
Results
310 glaucoma suspect and preperimetric glaucoma, and 177 perimetric glaucoma eyes were included. Eighty-nine eyes showed visual field progression and 101 eyes showed RNFL progression. The average time to detect visual field progression in those 89 eyes was 35±13 months; and to detect RNFL progression in those 101 eyes was 36±13 months. In multivariate Cox models, average and superior RNFL losses were associated with subsequent VFI loss in the entire cohort (every 10μm loss, HR=1.38,p=0.03; HR=1.20, p=0.01 respectively). Among the entire cohort of 487 eyes, 42 had significant VFI improvement and 55 had significant RNFL improvement (specificity 91.4% and 88.7%, respectively).
Conclusion
Structural progression is associated with functional progression in glaucoma suspect and glaucomatous eyes. Average and superior RNFL thickness may predict subsequent SAP loss.
doi:10.1016/j.ajo.2012.07.005
PMCID: PMC3525739  PMID: 23036570
retinal nerve fiber layer; visual field; glaucoma progression; hazard ratio
23.  Individual A-Scan Signal Normalization Between Two Spectral Domain Optical Coherence Tomography Devices 
Purpose.
We developed a method to normalize optical coherence tomography (OCT) signal profiles from two spectral-domain (SD) OCT devices so that the comparability between devices increases.
Methods.
We scanned 21 eyes from 14 healthy and 7 glaucoma subjects with two SD-OCT devices on the same day, with equivalent cube scan patterns centered on the fovea (Cirrus HD-OCT and RTVue). Foveola positions were selected manually and used as the center for registration of the corresponding images. A-scan signals were sampled 1.8 mm from the foveola in the temporal, superior, nasal, and inferior quadrants. After oversampling and rescaling RTVue data along the Z-axis to match the corresponding Cirrus data format, speckle noise reduction and amplitude normalization were applied. For comparison between normalized A-scan profiles, mean absolute difference in amplitude in percentage was measured at each sampling point. As a reference, the mean absolute difference between two Cirrus scans on the same eye also was measured.
Results.
The mean residual of the A-scan profile amplitude was reduced significantly after signal normalization (12.7% vs. 6.2%, P < 0.0001, paired t-test). All four quadrants also showed statistically significant reduction (all P < 0.0001). Mean absolute difference after normalization was smaller than the one between two Cirrus scans. No performance difference was detected between health and glaucomatous eyes.
Conclusions.
The reported signal normalization method successfully reduced the A-scan profile differences between two SD-OCT devices. This signal normalization processing may improve the direct comparability of OCT image analysis and measurement on various devices.
A novel signal normalization method for SD-OCT images was developed and tested to improve the direct comparability of image analysis and clinical measurements between devices. The A-scan profile differences between 2 SD-OCT devices were reduced significantly after normalization.
doi:10.1167/iovs.12-11484
PMCID: PMC3658265  PMID: 23611992
optical coherence tomography; image analysis; comparability
24.  Automated lamina cribrosa microstructural segmentation in optical coherence tomography scans of healthy and glaucomatous eyes 
Biomedical Optics Express  2013;4(11):2596-2608.
We demonstrate an automated segmentation method for in-vivo 3D optical coherence tomography (OCT) imaging of the lamina cribrosa (LC). Manual segmentations of coronal slices of the LC were used as a gold standard in parameter selection and evaluation of the automated technique. The method was validated using two prototype OCT devices; each had a subject cohort including both healthy and glaucomatous eyes. Automated segmentation of in-vivo 3D LC OCT microstructure performed comparably to manual segmentation and is useful for investigative research and in clinical quantification of the LC.
doi:10.1364/BOE.4.002596
PMCID: PMC3829553  PMID: 24298418
(100.2000) Digital image processing; (170.4470) Ophthalmology; (110.4500) Optical coherence tomography; (170.1610) Clinical applications; (330.4460) Ophthalmic optics and devices
25.  Optic Nerve Head and Retinal Nerve Fiber Layer Analysis 
Ophthalmology  2007;114(10):1937-1949.
Objective
To evaluate the current published literature on the use of optic nerve head (ONH) and retinal nerve fiber layer (RNFL) measurement devices in diagnosing open-angle glaucoma and detecting progression.
Methods
A search of peer-reviewed literature was conducted on February 15, 2006 in PubMed and the Cochrane Library for the period January 2003 to February 2006. The search was limited to studies of adults in English-language journals and yielded 442 citations. The panel reviewed the abstracts of these articles and selected 159 articles of possible clinical relevance for review. Of these 159 full-text articles, 82 were determined to be relevant for the first author and methodologist to review and rate according to the quality of evidence.
Results
There were no studies classified as having the highest level of evidence (level I). The ONH and RNFL imaging instruments reviewed in this assessment were determined to be highly effective in distinguishing eyes with glaucomatous visual field (VF) loss from normal eyes without VF loss, based on level II evidence. In addition, some studies demonstrated that parameters from ONH or RNFL imaging predicted the development of VF defects among glaucoma suspects. Studies on detecting glaucoma progression showed that although there was often agreement on progression between the structural and functional (VF) tests, a significant proportion of glaucoma patients progressed by either the structural or the functional test alone.
Conclusions
The ONH and RNFL imaging devices provide quantitative information for the clinician. Based on studies that have compared the various available technologies directly, there is no single imaging device that outperforms the others in distinguishing patients with glaucoma from controls. Ongoing advances in imaging and related software, as well as the impracticalities associated with obtaining and assessing optic nerve stereophotographs, have made imaging increasingly important in many practice settings. The information obtained from imaging devices is useful in clinical practice when analyzed in conjunction with other relevant parameters that define glaucoma diagnosis and progression.
doi:10.1016/j.ophtha.2007.07.005
PMCID: PMC3780976  PMID: 17908595

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